The aim of this experiment is to determine the species of mercury compound(s) that are the proximate toxic form by comparing the levels of inorganic (Hg) and methylmercury (MeHg) with morphometric changes. During the present grant period groups of primates were given 50 microgram Hg/kg/day "clinically subtoxic" levels of MeHg orally for 6, 12, 18 months and one group was given HgCl-2 for 3 months. MeHg freely passed through the blood-brain-barrier whereas in an HgCl-2 experiment it did not. Brain and tissue sampling has been completed and specimen analysis is underway. During the proposed grant period we plan to complete the speciation of mercury in 8 brain sites and do morphometry on contralateral paired samples. To date the mercury speciation studies done at the Karolinska Institute in Sweden have revealed that after 6 months exposure to the MeHg the brain Hg levels at 4 sites ranged from 3.0 to 4.0 micrograms/g and at 12 months the level was 4.2-5.0. The % inorganic Hg in the 4 brain sites was on average about 14% both at 6 and 12 months. We have the opportunity to use these valuable and unique samples already collected for mercury speciation in the pituitary, blood, kidney, muscle, fat and thyroid and other visceral tissues. This proposal couples the mercury analytical expertise and mercury metabolism knowledge of the Karolinska Institute group with the primate and morphometry expertise of the University of Washington. Morphometric measurements are also beginning. Extensive efforts at method development have established new and efficient procedures. We have found striking structural changes in the endothelial cells of the brain capillaries and down regulation of neuron organelles throughout. Complete analysis of the data is anticipated by the end of the proposed grant period.